{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T09:23:05Z","timestamp":1773307385249,"version":"3.50.1"},"reference-count":134,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T00:00:00Z","timestamp":1639958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"publisher","award":["R01 HL147081"],"award-info":[{"award-number":["R01 HL147081"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"publisher","award":["K01-HL130753"],"award-info":[{"award-number":["K01-HL130753"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Pew Biomedical Scholar Award","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"University of Utah 3i\/ Molecular Medicine","award":["Seed Funding"],"award-info":[{"award-number":["Seed Funding"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Emerging evidence indicates that perinatal infection and inflammation can influence the developing immune system and may ultimately affect long-term health and disease outcomes in offspring by perturbing tissue and immune homeostasis. We posit that perinatal inflammation influences immune outcomes in offspring by perturbing (1) the development and function of fetal-derived immune cells that regulate tissue development and homeostasis, and (2) the establishment and function of developing hematopoietic stem cells (HSCs) that continually generate immune cells across the lifespan. To disentangle the complexities of these interlinked systems, we propose the cochlea as an ideal model tissue to investigate how perinatal infection affects immune, tissue, and stem cell development. The cochlea contains complex tissue architecture and a rich immune milieu that is established during early life. A wide range of congenital infections cause cochlea dysfunction and sensorineural hearing loss (SNHL), likely attributable to early life inflammation. Furthermore, we show that both immune cells and bone marrow hematopoietic progenitors can be simultaneously analyzed within neonatal cochlear samples. Future work investigating the pathogenesis of SNHL in the context of congenital infection will therefore provide critical information on how perinatal inflammation drives disease susceptibility in offspring.<\/jats:p>","DOI":"10.3390\/cells10123596","type":"journal-article","created":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T08:43:32Z","timestamp":1639989812000},"page":"3596","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Early Life Inflammation and the Developing Hematopoietic and Immune Systems: The Cochlea as a Sensitive Indicator of Disruption"],"prefix":"10.3390","volume":"10","author":[{"given":"Kelly S.","family":"Otsuka","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7495-223X","authenticated-orcid":false,"given":"Christopher","family":"Nielson","sequence":"additional","affiliation":[{"name":"Division of Otolaryngology\u2014Head and Neck Surgery, University of Utah School of Medicine, Salt Lake City, UT 84112, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew A.","family":"Firpo","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Albert H.","family":"Park","sequence":"additional","affiliation":[{"name":"Division of Otolaryngology\u2014Head and Neck Surgery, University of Utah School of Medicine, Salt Lake City, UT 84112, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna E.","family":"Beaudin","sequence":"additional","affiliation":[{"name":"Division of Hematology and Hematologic Malignancies, University of Utah School of Medicine, Salt Lake City, UT 84112, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1822","DOI":"10.1038\/s41591-019-0675-0","article-title":"Chronic inflammation in the etiology of disease across the life span","volume":"25","author":"Furman","year":"2019","journal-title":"Nat. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1038\/nature01401","article-title":"Nature, nurture and human disease","volume":"421","author":"Chakravarti","year":"2003","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1038\/nrg2009","article-title":"The balance between heritable and environmental aetiology of human disease","volume":"7","author":"Hemminki","year":"2006","journal-title":"Nat. Rev. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1016\/S0140-6736(86)91340-1","article-title":"Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales","volume":"1","author":"Barker","year":"1986","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1093\/ije\/31.6.1235","article-title":"Fetal origins of adult disease: Strength of effects and biological basis","volume":"31","author":"Barker","year":"2002","journal-title":"Int. J. Epidemiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/S0140-6736(89)90710-1","article-title":"Weight in infancy and death from ischaemic heart disease","volume":"2","author":"Barker","year":"1989","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1055\/s-0029-1237424","article-title":"Developmental origins of health and disease: Brief history of the approach and current focus on epigenetic mechanisms","volume":"27","author":"Wadhwa","year":"2009","journal-title":"Semin. Reprod. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1038\/ni.3341","article-title":"The development and maintenance of resident macrophages","volume":"17","author":"Perdiguero","year":"2016","journal-title":"Nat. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.immuni.2016.07.014","article-title":"Cellular Barcoding Links B-1a B Cell Potential to a Fetal Hematopoietic Stem Cell State at the Single-Cell Level","volume":"45","author":"Kristiansen","year":"2016","journal-title":"Immunity"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1016\/j.immuni.2019.04.019","article-title":"Tissue-Resident Group 2 Innate Lymphoid Cells Differentiate by Layered Ontogeny and In Situ Perinatal Priming","volume":"50","author":"Schneider","year":"2019","journal-title":"Immunity"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1016\/j.celrep.2014.07.042","article-title":"Microglia modulate wiring of the embryonic forebrain","volume":"8","author":"Squarzoni","year":"2014","journal-title":"Cell Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e43271","DOI":"10.7554\/eLife.43271","article-title":"Macrophages restrict the nephrogenic field and promote endothelial connections during kidney development","volume":"8","author":"Munro","year":"2019","journal-title":"eLife"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/j.devcel.2019.01.021","article-title":"Endocardially Derived Macrophages Are Essential for Valvular Remodeling","volume":"48","author":"Shigeta","year":"2019","journal-title":"Dev. Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"E2384","DOI":"10.1073\/pnas.1400057111","article-title":"Yolk-sac-derived macrophages regulate fetal testis vascularization and morphogenesis","volume":"111","author":"DeFalco","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/j.it.2021.04.007","article-title":"Tissue-resident macrophages: Guardians of organ homeostasis","volume":"42","author":"Nobs","year":"2021","journal-title":"Trends Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1038\/s41423-020-00541-3","article-title":"Macrophages and the maintenance of homeostasis","volume":"18","author":"Mosser","year":"2021","journal-title":"Cell Mol. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Gordon, S., and Pluddemann, A. (2017). Tissue macrophages: Heterogeneity and functions. BMC Biol., 15.","DOI":"10.1186\/s12915-017-0392-4"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1136\/bmj.299.6710.1259","article-title":"Hay fever, hygiene, and household size","volume":"299","author":"Strachan","year":"1989","journal-title":"BMJ"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"123","DOI":"10.3389\/fimmu.2020.00123","article-title":"Training the Fetal Immune System Through Maternal Inflammation-A Layered Hygiene Hypothesis","volume":"11","author":"Apostol","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1007\/s00281-017-0654-9","article-title":"Vaccine responses in newborns","volume":"39","author":"Saso","year":"2017","journal-title":"Semin. Immunopathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1056\/NEJMoa1007302","article-title":"Exposure to environmental microorganisms and childhood asthma","volume":"364","author":"Ege","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1203\/PDR.0b013e318217638a","article-title":"The role of microbes in developmental immunologic programming","volume":"69","author":"Kaplan","year":"2011","journal-title":"Pediatr. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/S1473-3099(11)70341-3","article-title":"Uninfected but not unaffected: Chronic maternal infections during pregnancy, fetal immunity, and susceptibility to postnatal infections","volume":"12","author":"Dauby","year":"2012","journal-title":"Lancet Infect. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.exphem.2017.12.008","article-title":"Many layers of embryonic hematopoiesis: New insights into B-cell ontogeny and the origin of hematopoietic stem cells","volume":"60","author":"Hadland","year":"2018","journal-title":"Exp. Hematol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2994","DOI":"10.1084\/jem.20181206","article-title":"Epidermal \u03b3\u03b4 T cells originate from yolk sac hematopoiesis and clonally self-renew in the adult","volume":"215","author":"Gentek","year":"2018","journal-title":"J. Exp. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1016\/j.immuni.2018.04.025","article-title":"Hemogenic Endothelial Fate Mapping Reveals Dual Developmental Origin of Mast Cells","volume":"48","author":"Gentek","year":"2018","journal-title":"Immunity"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.immuni.2016.02.024","article-title":"Tissue-Resident Macrophage Ontogeny and Homeostasis","volume":"44","author":"Ginhoux","year":"2016","journal-title":"Immunity"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1038\/s41586-020-2316-7","article-title":"Deciphering human macrophage development at single-cell resolution","volume":"582","author":"Bian","year":"2020","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1038\/nri3920","article-title":"Regulation of macrophage development and function in peripheral tissues","volume":"15","author":"Lavin","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1016\/j.cell.2014.11.018","article-title":"Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment","volume":"159","author":"Lavin","year":"2014","journal-title":"Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/ni.3325","article-title":"The role of the local environment and epigenetics in shaping macrophage identity and their effect on tissue homeostasis","volume":"17","author":"Amit","year":"2016","journal-title":"Nat. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1016\/j.immuni.2013.04.004","article-title":"Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes","volume":"38","author":"Hashimoto","year":"2013","journal-title":"Immunity"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1002\/(SICI)1096-9861(19970106)377:1<70::AID-CNE7>3.0.CO;2-G","article-title":"Development of microglia in the prenatal rat hippocampus","volume":"377","author":"Dalmau","year":"1997","journal-title":"J. Comp. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1002\/glia.20459","article-title":"Microglial Control of Neuronal Death and Synaptic Properties","volume":"55","author":"Alain","year":"2007","journal-title":"Glia"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1126\/science.1202529","article-title":"Synaptic pruning by microglia is necessary for normal brain development","volume":"333","author":"Paolicelli","year":"2011","journal-title":"Science"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.cell.2018.07.048","article-title":"Self-Maintaining Gut Macrophages Are Essential for Intestinal Homeostasis","volume":"175","author":"Verheijden","year":"2018","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2072","DOI":"10.1016\/j.immuni.2021.07.003","article-title":"Resident cardiac macrophages mediate adaptive myocardial remodeling","volume":"54","author":"Wong","year":"2021","journal-title":"Immunity"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1016\/j.cell.2017.03.050","article-title":"Macrophages Facilitate Electrical Conduction in the Heart","volume":"169","author":"Hulsmans","year":"2017","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1977","DOI":"10.1084\/jem.20131199","article-title":"Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF","volume":"210","author":"Guilliams","year":"2013","journal-title":"J. Exp. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1038\/s41590-018-0272-2","article-title":"Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction","volume":"20","author":"Dick","year":"2019","journal-title":"Nat. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1016\/j.immuni.2016.02.017","article-title":"Yolk Sac Macrophages, Fetal Liver, and Adult Monocytes Can Colonize an Empty Niche and Develop into Functional Tissue-Resident Macrophages","volume":"44","author":"Saelens","year":"2016","journal-title":"Immunity"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1084\/jem.20180247","article-title":"Peripherally derived macrophages can engraft the brain independent of irradiation and maintain an identity distinct from microglia","volume":"215","author":"Cronk","year":"2018","journal-title":"J. Exp. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.immuni.2017.08.018","article-title":"Tissue-Resident Macrophages in Pancreatic Ductal Adenocarcinoma Originate from Embryonic Hematopoiesis and Promote Tumor Progression","volume":"47","author":"Zhu","year":"2017","journal-title":"Immunity"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1111\/j.1365-2141.1970.tb01443.x","article-title":"Ontogeny of the haemopoietic system: Yolk sac origin of in vivo and in vitro colony forming cells in the developing mouse embryo","volume":"18","author":"Moore","year":"1970","journal-title":"Br. J. Haematol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3965","DOI":"10.1002\/1873-3468.12459","article-title":"Hematopoietic stem cell-independent hematopoiesis: Emergence of erythroid, megakaryocyte, and myeloid potential in the mammalian embryo","volume":"590","author":"Palis","year":"2016","journal-title":"FEBS Lett."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/1074-7613(94)90081-7","article-title":"Development of hematopoietic stem cell activity in the mouse embryo","volume":"1","author":"Muller","year":"1994","journal-title":"Immunity"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1016\/S0092-8674(00)80165-8","article-title":"Definitive hematopoiesis is autonomously initiated by the AGM region","volume":"86","author":"Medvinsky","year":"1996","journal-title":"Cell"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0070-2153(07)00001-4","article-title":"Ontogeny of erythropoiesis in the mammalian embryo","volume":"82","author":"McGrath","year":"2008","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1016\/0092-8674(89)90748-4","article-title":"Toward a layered immune system","volume":"59","author":"Herzenberg","year":"1989","journal-title":"Cell"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.cell.2018.05.029","article-title":"Developmental Origin Governs CD8","volume":"174","author":"Smith","year":"2018","journal-title":"Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1038\/nature13824","article-title":"Clonal dynamics of native haematopoiesis","volume":"514","author":"Sun","year":"2014","journal-title":"Nature"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1038\/nature14242","article-title":"Fundamental properties of unperturbed haematopoiesis from stem cells in vivo","volume":"518","author":"Busch","year":"2015","journal-title":"Nature"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1016\/j.stem.2016.08.013","article-title":"A Transient Developmental Hematopoietic Stem Cell Gives Rise to Innate-like B and T Cells","volume":"19","author":"Beaudin","year":"2016","journal-title":"Cell Stem Cell"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1182\/blood-2017-06-780882","article-title":"Inflammation: A key regulator of hematopoietic stem cell fate in health and disease","volume":"130","author":"Pietras","year":"2017","journal-title":"Blood"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.stem.2015.07.007","article-title":"Inflammation-Induced Emergency Megakaryopoiesis Driven by Hematopoietic Stem Cell-like Megakaryocyte Progenitors","volume":"17","author":"Haas","year":"2015","journal-title":"Cell Stem Cell"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3023","DOI":"10.1002\/stem.1799","article-title":"Type II interferon promotes differentiation of myeloid-biased hematopoietic stem cells","volume":"32","author":"Matatall","year":"2014","journal-title":"Stem Cells"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1038\/ncb3346","article-title":"Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal","volume":"18","author":"Pietras","year":"2016","journal-title":"Nat. Cell Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.stem.2012.02.007","article-title":"Hematopoietic stem cell subtypes expand differentially during development and display distinct lymphopoietic programs","volume":"10","author":"Benz","year":"2012","journal-title":"Cell Stem Cell"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2808","DOI":"10.1172\/JCI28310","article-title":"Hematopoietic stem cells proliferate until after birth and show a reversible phase-specific engraftment defect","volume":"116","author":"Bowie","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"5878","DOI":"10.1073\/pnas.0700460104","article-title":"Identification of a new intrinsically timed developmental checkpoint that reprograms key hematopoietic stem cell properties","volume":"104","author":"Bowie","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1182\/blood.V97.2.419","article-title":"CD34 expression on long-term repopulating hematopoietic stem cells changes during developmental stages","volume":"97","author":"Matsuoka","year":"2001","journal-title":"Blood"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"14541","DOI":"10.1073\/pnas.261562798","article-title":"Flk-2 is a marker in hematopoietic stem cell differentiation: A simple method to isolate long-term stem cells","volume":"98","author":"Christensen","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1001\/archinternmed.2008.597","article-title":"Prevalence of age-related hearing loss in older adults: Blue Mountains Study","volume":"169","author":"Gopinath","year":"2009","journal-title":"Arch. Intern. Med."},{"key":"ref_64","first-page":"1","article-title":"Summary health statistics for U.S. adults: National health interview survey, 2012","volume":"10","author":"Blackwell","year":"2014","journal-title":"Vital Health Stat."},{"key":"ref_65","unstructured":"Centers for Disease Control and Prevention (2010). Identifying infants with hearing loss\u2014United States, 1999\u20132007. MMWR Morb. Mortal. Wkly. Rep., 59, 220\u2013223."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1016\/S0140-6736(05)71047-3","article-title":"Sensorineural hearing loss in children","volume":"365","author":"Smith","year":"2005","journal-title":"Lancet"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"917","DOI":"10.15585\/mmwr.mm6534e3","article-title":"Hearing Loss in Infants with Microcephaly and Evidence of Congenital Zika Virus Infection - Brazil, November 2015\u2013May 2016","volume":"65","author":"Leal","year":"2016","journal-title":"MMWR Morb. Mortal. Wkly. Rep."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1080\/00365540802308431","article-title":"Congenital CMV infection: Prevalence in newborns and the impact on hearing deficit","volume":"40","author":"Engman","year":"2008","journal-title":"Scand. J. Infect. Dis."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1002\/rmv.535","article-title":"Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection","volume":"17","author":"Kenneson","year":"2007","journal-title":"Rev. Med. Virol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1542\/peds.2006-3441","article-title":"Newborn hearing screening and detection of congenital cytomegalovirus infection","volume":"121","author":"Stehel","year":"2008","journal-title":"Pediatrics"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"S6","DOI":"10.1016\/j.jcv.2009.09.002","article-title":"Congenital cytomegalovirus (CMV) epidemiology and awareness","volume":"46","author":"Cannon","year":"2009","journal-title":"J. Clin. Virol."},{"key":"ref_72","unstructured":"Stratton, K.R., Durch, J.S., and Lawrence, R.S. (2001). Vaccines for the 21st Century: A Tool for Decisionmaking, National Academies Press."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1097\/INF.0b013e31825b9524","article-title":"Hearing loss in perinatally HIV-infected and HIV-exposed but uninfected children and adolescents","volume":"31","author":"Torre","year":"2012","journal-title":"Pediatr. Infect Dis. J."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/S0140-6736(82)92677-0","article-title":"Consequences of confirmed maternal rubella at successive stages of pregnancy","volume":"2","author":"Miller","year":"1982","journal-title":"Lancet"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e20183095","DOI":"10.1542\/peds.2018-3095","article-title":"Hearing Loss With Congenital Cytomegalovirus Infection","volume":"144","author":"Foulon","year":"2019","journal-title":"Pediatrics"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1177\/0194599818758247","article-title":"Hearing Trajectory in Children with Congenital Cytomegalovirus Infection","volume":"158","author":"Lanzieri","year":"2018","journal-title":"Otolaryngol..\u2013Head Neck Surg."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"e20162610","DOI":"10.1542\/peds.2016-2610","article-title":"Hearing Loss in Children With Asymptomatic Congenital Cytomegalovirus Infection","volume":"139","author":"Lanzieri","year":"2017","journal-title":"Pediatrics"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Martinez-Gomez, E., Perez-Carpena, P., Flook, M., and Lopez-Escamez, J.A. (2020). A Systematic Review on the Association of Acquired Human Cytomegalovirus Infection with Hearing Loss. J. Clin. Med., 9.","DOI":"10.3390\/jcm9124011"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Nomoto, H., Ishikane, M., Nakamoto, T., Ohta, M., Morioka, S., Yamamoto, K., Kutsuna, S., Tezuka, S., Kunimatsu, J., and Ohmagari, N. (2020). Conjunctivitis, the key clinical characteristic of adult rubella in Japan during two large outbreaks, 2012\u20132013 and 2018\u20132019. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0231966"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1136\/adc.64.9.1280","article-title":"Onset and severity of hearing loss due to congenital rubella infection","volume":"64","author":"Wild","year":"1989","journal-title":"Arch. Dis. Child."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1542\/peds.90.6.862","article-title":"Progressive hearing loss in infants with asymptomatic congenital cytomegalovirus infection","volume":"90","author":"Williamson","year":"1992","journal-title":"Pediatrics"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1016\/S0022-3476(97)70248-8","article-title":"Progressive and fluctuating sensorineural hearing loss in children with asymptomatic congenital cytomegalovirus infection","volume":"130","author":"Fowler","year":"1997","journal-title":"J. Pediatr."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"16094","DOI":"10.1038\/nrdp.2016.94","article-title":"Congenital hearing loss","volume":"3","author":"Korver","year":"2017","journal-title":"Nat. Rev. Dis. Primers."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.ijporl.2009.01.012","article-title":"A systematic review of neonatal toxoplasmosis exposure and sensorineural hearing loss","volume":"73","author":"Brown","year":"2009","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1086\/501360","article-title":"Outcome of Treatment for Congenital Toxoplasmosis, 1981\u20132004: The National Collaborative Chicago-Based, Congenital Toxoplasmosis Study","volume":"42","author":"McLeod","year":"2006","journal-title":"Clin. Infect. Dis."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1177\/000348947908800202","article-title":"Treatment of Syphilitic Hearing Loss:Combined Penicillin and Steroid Therapy in 29 Patients","volume":"88","author":"Zoller","year":"1979","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/j.vaccine.2020.12.079","article-title":"Immunogenicity, duration of protection, effectiveness and safety of rubella containing vaccines: A systematic literature review and meta-analysis","volume":"39","author":"Desai","year":"2021","journal-title":"Vaccine"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"e177","DOI":"10.1016\/S1473-3099(17)30143-3","article-title":"Congenital cytomegalovirus infection in pregnancy and the neonate: Consensus recommendations for prevention, diagnosis, and therapy","volume":"17","author":"Rawlinson","year":"2017","journal-title":"Lancet Infect. Dis."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Bradford, R.D., Yoo, Y.-G., Golemac, M., Pugel, E.P., Jonjic, S., and Britt, W.J. (2015). Murine CMV-induced hearing loss is associated with inner ear inflammation and loss of spiral ganglia neurons. PLoS Pathog., 11.","DOI":"10.1371\/journal.ppat.1004774"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/s13365-011-0024-7","article-title":"Cytomegalovirus-induced sensorineural hearing loss with persistent cochlear inflammation in neonatal mice","volume":"17","author":"Schachtele","year":"2011","journal-title":"J. Neurovirol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/j.otohns.2007.03.044","article-title":"Macrophage inflammatory proteins in cytomegalovirus-related inner ear injury","volume":"137","author":"Schraff","year":"2007","journal-title":"Otolaryngol.\u2013Head Neck Surg."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"552","DOI":"10.3389\/fimmu.2014.00552","article-title":"Immunity to cytomegalovirus in early life","volume":"5","author":"Huygens","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1038\/cmi.2014.51","article-title":"Immunobiology of congenital cytomegalovirus infection of the central nervous system-the murine cytomegalovirus model","volume":"12","author":"Slavuljica","year":"2015","journal-title":"Cell Mol. Immunol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.disamonth.2013.01.005","article-title":"Clinical measures of auditory function: The cochlea and beyond","volume":"59","author":"Baiduc","year":"2013","journal-title":"Dis. Mon."},{"key":"ref_95","first-page":"72","article-title":"Blood-labyrinth barrier and fluid dynamics of the inner ear","volume":"7","author":"Juhn","year":"2001","journal-title":"Int. Tinnitus. J."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/BF00455222","article-title":"Evidence of mechanical nonlinearity and frequency selective wave amplification in the cochlea","volume":"224","author":"Kemp","year":"1979","journal-title":"Arch. Otorhinolaryngol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/0165-5876(92)90080-9","article-title":"Experience with the audiologic assessment of infants and toddlers","volume":"23","author":"Gravel","year":"1992","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"281","DOI":"10.3109\/00016486909125453","article-title":"Visual reinforcement audiometry","volume":"67","author":"Liden","year":"1969","journal-title":"Acta Otolaryngol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.heares.2016.12.010","article-title":"Translational issues in cochlear synaptopathy","volume":"349","author":"Hickox","year":"2017","journal-title":"Hear. Res."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"14077","DOI":"10.1523\/JNEUROSCI.2845-09.2009","article-title":"Adding insult to injury: Cochlear nerve degeneration after \u201ctemporary\u201d noise-induced hearing loss","volume":"29","author":"Kujawa","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"P230","DOI":"10.1177\/0194599812451426a334","article-title":"Development of a Murine Model for CMV-Induced Hearing Loss","volume":"147","author":"Patel","year":"2012","journal-title":"Otolaryngol.\u2013Head Neck Surg."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"110275","DOI":"10.1016\/j.ijporl.2020.110275","article-title":"Role of cochlear synaptopathy in cytomegalovirus infected mice and in children","volume":"138","author":"Almishaal","year":"2020","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Almishaal, A.A., Mathur, P.D., Hillas, E., Chen, L., Zhang, A., Yang, J., Wang, Y., Yokoyama, W.M., Firpo, M.A., and Park, A.H. (2017). Natural killer cells attenuate cytomegalovirus-induced hearing loss in mice. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006599"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/s10162-016-0606-4","article-title":"Cytomegalovirus (CMV) Infection Causes Degeneration of Cochlear Vasculature and Hearing Loss in a Mouse Model","volume":"18","author":"Carraro","year":"2017","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1177\/000348948409300211","article-title":"Immunology of the inner ear: Evidence of local antibody production","volume":"93","author":"Harris","year":"1984","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Nyberg, S., Abbott, N.J., Shi, X., Steyger, P.S., and Dabdoub, A. (2019). Delivery of therapeutics to the inner ear: The challenge of the blood-labyrinth barrier. Sci. Transl. Med., 11.","DOI":"10.1126\/scitranslmed.aao0935"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"285","DOI":"10.3389\/fncel.2019.00285","article-title":"Advances and challenges in pharmaceutical therapies to prevent and repair cochlear injuries from noise","volume":"13","author":"Bielefeld","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"ref_108","first-page":"49","article-title":"The role of monocytes and macrophages in the dynamic permeability of the blood-perilymph barrier","volume":"374","author":"Hirose","year":"2019","journal-title":"Physiol. Behav."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1002\/cne.20619","article-title":"Mononuclear phagocytes migrate into the murine cochlea after acoustic trauma","volume":"489","author":"Hirose","year":"2005","journal-title":"J. Comp. Neurol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"15167","DOI":"10.1038\/s41598-020-72181-6","article-title":"The immune response after noise damage in the cochlea is characterized by a heterogeneous mix of adaptive and innate immune cells","volume":"10","author":"Rai","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s00441-010-1040-2","article-title":"Resident macrophages in the cochlear blood-labyrinth barrier and their renewal via migration of bone-marrow-derived cells","volume":"342","author":"Shi","year":"2010","journal-title":"Cell Tissue Res."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1758","DOI":"10.1002\/jnr.21625","article-title":"Bone marrow-derived cells expressing Iba1 are constitutively present as resident tissue macrophages in the mouse cochlea","volume":"86","author":"Okano","year":"2008","journal-title":"J. Neurosci. Res."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"42079","DOI":"10.1038\/srep42079","article-title":"Gfi1Cre mice have early onset progressive hearing loss and induce recombination in numerous inner ear non-hair cells","volume":"7","author":"Matern","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.3389\/fneur.2019.01115","article-title":"Early Development of Resident Macrophages in the Mouse Cochlea Depends on Yolk Sac Hematopoiesis","volume":"10","author":"Kishimoto","year":"2019","journal-title":"Front. Neurol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/S0378-5955(98)00214-7","article-title":"Development of blood-labyrinth barrier in the semicircular canal ampulla of the rat","volume":"129","author":"Suzuki","year":"1999","journal-title":"Hear. Res."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.heares.2005.11.011","article-title":"Uptake of fluorescent gentamicin by vertebrate sensory cells in vivo","volume":"213","author":"Dai","year":"2006","journal-title":"Hear. Res."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.3389\/fneur.2019.01244","article-title":"Csf1 Signaling Regulates Maintenance of Resident Macrophages and Bone Formation in the Mouse Cochlea","volume":"10","author":"Okano","year":"2019","journal-title":"Front. Neurol."},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Booth, J.S., and Toapanta, F.R. (2021). B and T Cell Immunity in Tissues and Across the Ages. Vaccines, 9.","DOI":"10.3390\/vaccines9010024"},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Hashemi, E., and Malarkannan, S. (2020). Tissue-Resident NK Cells: Development, Maturation, and Clinical Relevance. Cancers, 12.","DOI":"10.3390\/cancers12061553"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1146\/annurev-immunol-042617-053214","article-title":"Tissue-Resident T Cells and Other Resident Leukocytes","volume":"37","author":"Masopust","year":"2019","journal-title":"Annu. Rev. Immunol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"2058","DOI":"10.1038\/jid.2011.179","article-title":"Visualizing the neutrophil response to sterile tissue injury in mouse dermis reveals a three-phase cascade of events","volume":"131","author":"Ng","year":"2011","journal-title":"J. Investig. Dermatol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"e01659","DOI":"10.7554\/eLife.01659","article-title":"Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells","volume":"3","author":"Sojka","year":"2014","journal-title":"eLife"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1016\/j.cell.2020.01.022","article-title":"Tissue Determinants of Human NK Cell Development, Function, and Residence","volume":"180","author":"Dogra","year":"2020","journal-title":"Cell"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"59","DOI":"10.4049\/immunohorizons.2000067","article-title":"Tissue-Resident Memory T Cells in the Lungs Protect against Acute Respiratory Syncytial Virus Infection","volume":"5","author":"Luangrath","year":"2021","journal-title":"Immunohorizons"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"755","DOI":"10.2217\/fvl-2020-0132","article-title":"Brain tissue-resident immune memory cells are required for long-term protection against CNS infection with rabies virus","volume":"15","author":"Lebrun","year":"2020","journal-title":"Future Virol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1128\/IAI.01378-15","article-title":"Tissue-Resident T Cells as the Central Paradigm of Chlamydia Immunity","volume":"84","author":"Johnson","year":"2016","journal-title":"Infect. Immun."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"2778","DOI":"10.1084\/jem.20181468","article-title":"Neutrophils instruct homeostatic and pathological states in naive tissues","volume":"215","author":"Li","year":"2018","journal-title":"J. Exp. Med."},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Jan, T.A., Chai, R., Sayyid, Z.N., and Cheng, A.G. (2011). Isolating LacZ-expressing Cells from Mouse Inner Ear Tissues using Flow Cytometry. JoVE, e3432.","DOI":"10.3791\/3432-v"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"2801","DOI":"10.1002\/lary.24090","article-title":"A comparison of different murine models for cytomegalovirus-induced sensorineural hearing loss","volume":"123","author":"Wang","year":"2013","journal-title":"Laryngoscope"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"e128878","DOI":"10.1172\/jci.insight.128878","article-title":"Virus-induced cochlear inflammation in newborn mice alters auditory function","volume":"4","author":"Sung","year":"2019","journal-title":"JCI Insight"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1177\/0194599820901485","article-title":"Role of Free Radical Formation in Murine Cytomegalovirus-Induced Hearing Loss","volume":"162","author":"Pecha","year":"2020","journal-title":"Otolaryngol.\u2013Head Neck Surg."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"102270","DOI":"10.1016\/j.amjoto.2019.08.001","article-title":"Cytomegalovirus-induced pathology in human temporal bones with congenital and acquired infection","volume":"40","author":"Tsuprun","year":"2019","journal-title":"Am. J. Otolaryngol."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1007\/s00401-011-0895-y","article-title":"Inner ear lesions in congenital cytomegalovirus infection of human fetuses","volume":"122","author":"Teissier","year":"2011","journal-title":"Acta Neuropathol."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1002\/lary.28134","article-title":"Effects of ganciclovir treatment in a murine model of cytomegalovirus-induced hearing loss","volume":"130","author":"Haller","year":"2020","journal-title":"Laryngoscope"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/12\/3596\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:49:52Z","timestamp":1760168992000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/12\/3596"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,20]]},"references-count":134,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["cells10123596"],"URL":"https:\/\/doi.org\/10.3390\/cells10123596","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,20]]}}}